Problematic alcohol drinking (the extreme form of which is alcohol dependence) is an etiologically and clinically heterogeneous phenomenon that is most likely caused by an interaction of genetic predisposition and environmental exposures. Recognition of this heterogeneity has led to a variety of attempts to develop multivariate, multi-dimensional typologies of alcohol dependence (AD). Several studies have shown that subgroups of alcoholics may respond differently to treatment with serotonergic medications and perhaps with naltrexone (NTX). The research component of this proposal is built upon on an on-going NIAAA-funded study on the efficacy of 12 weeks of randomly assigned treatment with NTX or cognitive behavioral therapy (CBT) or the two combined, in a population of problem-drinking men who have sex with men (MSM) in New York City and vicinity. The proposed K award will enable the candidate to study the genetic underpinnings of the individual treatment responses in this unique risk group whose social milieu and networks are more likely to involve the consumption of alcohol. Their disease manifestations are similar in many respects to those of the majority of hidden problem-drinkers in that they are generally high functioning and do not normally seek treatments that advocate complete abstinence as their goal. The objectives of the proposed study are to determine whether genetic variants in the genes encoding the serotonin transporter (5-HTTLPR), mu-opioid receptor (OPRM1), and GABA-A receptor subunit (GABRA2) are associated with the course and outcome of pharmacotherapy with naltrexone and/or cognitive behavioral psychotherapy treatment in this unique population. The candidate genes and polymorphisms were chosen based on recent studies showing small-to-moderate effects of these genetic variants on certain alcohol-related clinical characteristics. In addition to standard outcome measures, we propose to utilize a novel data collection technology, Interactive Voice Response, to collect data on daily relations among mood, craving, self-efficacy, motivation, and drinking. To augment the practicum in mastering the skills of design and implement of clinical trials for the candidate and to test the potential use of a new medication for moderation of drinking in a specific population, the research plan also includes a pilot study on the efficacy and safety of oral topiramate (200 mg/day) in the same high functioning MSM problem drinking group. Overall, the data generated from the studies and the methodology used will serve as a foundation for future studies of personalized treatments for AUD. This Mentored Patient-Oriented Research Career Award application will provide Andrew C. Chen, MD, PhD, a well trained psychiatrist and molecular neuroscientist, with the necessary time, mentorship and training to conduct high-quality clinical translational research, including pharmacogenetic approaches, to develop personalized treatments for alcohol use disorders (AUD).